Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by progressive loss of lung function with subsequent increasing breathlessness and worsening quality of life. The condition is due to an admixture of emphysema and airways remodeling. This unpredictable mixture of tissue pathology is indiscernible with conventional spirometric measures of lung function. Computed tomography (CT) is increasingly being used to characterize emphysema and airway disease in COPD. However, classic CT measures of the airways are limited for assessing airway remodeling. The applicant has developed novel CT metrics of airways that provide insight into both the mechanical properties of airways and their disappearance in advanced emphysema. In this career development proposal, the applicant hypothesizes that CT airway characteristics can independently predict clinical manifestations and disease progression in COPD. Aim 1 of this application involves the histologic validation of two novel CT metrics of airways. The goal of Aim 2 is to analyze chest CT scans from the COP Gene Study and correlate airway distensibility (a measure of the change in airway inner diameter from end tidal breathing to full inspiration) and total airway count (a measure of proximal airway drop out) with spirometric parameters, clinical manifestations of disease, and exercise capacity. In Aim 3, the applicant will measure total airway count on CT scans from the ECLIPSE Study and then determine the ability of total airway count to predict decline in lung function, COPD exacerbations, and mortality. These CT-based airway metrics have the potential to be used as non-invasive biomarkers for clinical investigation in COPD. The aims of this research proposal are possible through the active collaboration of Dr. Bartolome Celli, M.D., an internationally renowned clinical investigator in COPD and Dr. George Washko M.D., M.M.Sc., a prominent physician investigator in quantitative CT imaging. (End of Abstract)